DESCRIPTION 3 OVERALL CRITIQUE 3 SPORE PROGRAM ORGANIZATION AND CAPABILITIES 6 SCIENTIFIC COLLABORATIONS 9 ADDITIONAL REVIEW CRITERIA 10 PROTECTION OF HUMAN SUBJECTS 10 VERTEBRATE ANIMALS 11 BIOHAZARDS 11 FOREIGN ORGANIZATIONS 11 INDIVIDUAL PROJECTS AND CORES 12 PROJECT 1: Potentiating the Effects of Targeted and Cytotoxic Agents on Cell-Based Immunotherapy n Melanoma 12 PROJECT 2: Abrogation of Therapeutic Escape Pathways in BRAF Mutant Melanoma 16 PROJECT 3: Augmenting the Immunogenicity of Melanoma through Manipulation of Histone Deacetylses (HDACs) 22 PROJECT 4: Prospective Study of the Associations between Cutaneous Papillomavirus and Polyomavirus Infections and Squamous Cell Carcinoma 27 CORE A: Tissue, Pathology and Bioinformatics Core 33 CORE B: Biostatistics Core 36 CORE C: Administration and Clinical Trials Core 39 DEVELOPMENTAL RESEARCH PROGRAM 41 CAREER DEVELOPMENT PROGRAM 43 COMMITTEE BUDGET RECOMMENDATIONS 47 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): The long-range goal of the Moffitt Skin SPORE is to promote progress in the prevention and treatment of cutaneous malignancies based on developments in our laboratories that are applied to innovative clinical trials. The bench work in each project is a necessary precursor to carrying out the trials associated with the SPORE, since those investigations will explore new biomarkers and correlative assays that are integral to the translational importance of each trial. The translational endpoints of the trials will provide new data that will lead to further laboratory developments that in turn will iteratively lead to strategies for improved trials. The bench-to-bedside-to-bench interaction is imbedded within the core values of Moffitt as a free-standing cancer center, in which a dedicated group of clinician-investigators with extensive experience in the management of melanoma and non-melanoma skin cancer will work with an outstanding group of basic scientists to accelerate the movement of ideas out of the laboratory to the clinic. The support of the Moffitt Cancer Center and its Comprehensive Melanoma Research Center will be crucial to fulfilling this goal, providing ancillary resources and infrastructure to insure the success of the Moffitt Skin SPORE goals. In this Skin SPORE application, the melanoma projects will focus on research in melanoma biology, immunity and signaling that create opportunities to potentiate current and developing clinical approaches to the treatment of cutaneous malignancies. Project 1 will pave the way for larger randomized phase II or phase III trials of adoptive immunotherapy with tumor infiltrating lymphocytes to support the inclusion of BRAF agents with this promising therapy, based on innovative approaches for how these two modalities should be brought together. Project 2 will support the use of Hsp90 inhibitors to overcome resistance to BRAF inhibition in phase II and III trials, redefining how we look at resistance to targeted therapies. Project 3 represents a paradigm shift that employs epigenetic manipulation to alter how we use immunotherapy, and will justify phase II efficacy testing of the combination of HDAc inhibitors with ipilimumab and other immune stimulants. Project 4 will focus on Human Papilloma Virus (HPV) and Merkel's Cell Polyoma Virus (MCPV) types that could potentially play a key role in the development of non-melanoma skin cancers. We expect that data from Project 4 will justify developing new prevention trials of vaccines for HPV and MCPV to prevent squamous and/or basal cell cancers of the skin. The success of each project and the Moffitt Skin SPORE as a whole will have a major impact on the management of cutaneous malignancies.